Bioprecursors for percutaneous application

ABSTRACT

The invention concerns a bioprecursor of formula (I), wherein A 1  and A 2  represent independently of each other a radical derived from a molecule capable of being used in dermatology or in cosmetology; X and Y represent independently of each other a hydrogen atom, a hydroxy group or a C 1 -C 20  alkyl group; and n represents an integer between 0 and 10.

[0001] The present invention relates to a cosmetic or pharmaceuticalcomposition for cutaneous application, containing a compound capable ofreleasing two active molecules (in particular vitamins) via the actionof an esterase activity contained in the skin, the spacer possiblyintroducing an additional effect (for example moisturizing effect ofhydroxy acid).

[0002] It has previously been shown, using two sources of cutaneousenzymes, that this enzyme is indeed capable of recognizing andhydrolyzing succinic esters, thus allowing slow release of the activesubstance, without an accumulation effect (M. P. Mora et al., Chem.Phys. Lipids (1999), 101, 255-265, J. R. Trevithick et al., Biochem.Mol. Biol. Int. (1999), 47, 509-511).

[0003] The bioprecursor strategy has previously been used for therelease of active agents, especially in the following cases:

[0004] release of retinol from its ester with palmitic acid.

[0005] Many compounds are used in dermatology, among which the followingwill be selected:

[0006] moisturizers, or more specifically agents for controlling skinperspiration, such as saccharides (glucose, sorbitol or hyaluronicacid), but also glycerol and α-hydroxy acids, or even ceramides of plantorigin, which moisturize via their polar portion. Among the hydroxyacids, L-ascorbic acid is an agent of choice, since it combines thisprimary property with other effects: an antioxidant effect and also theability to stimulate collagen synthesis (and thus the synthesis ofelastic fibres) via a specific increase in the level of mRNA coding forthe three pro-α chains. Furthermore, ascorbic acid activates the enzymethat effects the formation of collagen from procollagen (S. R. Pinel etal., Arch. Dermatol. (1987), 123, 1684-1687);

[0007] antioxidants: it is known that they are essential to avoid thedegradation of lipids via the action of radicals and also other damageto biomolecules of the skin surface, this damage resulting in theformation of wrinkles. Among the main free-radical scavengers found aretocopherols, flavonoids, ascorbic acid and metal-chelating agents, whichblockade the oxidation reactions catalyzed by said metals;

[0008] agents for controlling differentiation: the most important isvitamin A or retinol, since a deficiency is reflected byhyperkeratinization and also atrophy of the sebaceous glands and thesweat glands. Retinol is not used in its native form, but after twoenzymatic oxidations, the first reversible, which converts it intoretinal, and the second irreversible, converting it into retinoic acid,which is the active form that acts on the nuclear receptors. It isstored in the form of linoleic and palmitic esters. A supply may beprovided in the form of esters or in the form of retinol linked to avector. It is known that the action of retinoic acid is manifold:activator of cell metabolism and control of keratinization, antioxidantand thus prevention of the formation of wrinkles, action, on the dermis,on the metabolism of fibroblasts via two effects: inhibition of thecollagen-degrading enzymes (collagenases) and stimulation ofglucosaminoglycans which increase the content of collagen and thusincrease the elasticity of the skin;

[0009] vitamin D, which, besides its action on phosphocalcic metabolism,exerts via its biologically active form, calcitriol, effects on cellproliferation and differentiation. Specifically, incubation of humankeratinocytes with calcitriol results in a decrease in theirproliferation and induction of their terminal differentiation (M. F.Holick et al., Arch. Dermatol. (1987), 123, 1677-1683). Calcitriol isalso a powerful immunosuppressant, which inhibits lymphocyte activationand the production of immunoglobulins (M. Bagot et al., Br. J. Dermatol.(1994), 130, 424-431).

[0010] The direct topical use of these derivatives comes up against acertain number of difficulties, due to their lack of stability over timeand to light, and secondary effects (pro-oxidizing and irritationeffects) often resulting from local overconcentrations of the activemolecules.

[0011] The value of improving the bioavailability of active agentsconveyed in the form of a precursor in which they are associated, andthus of avoiding their harmful effects caused by accumulation, may thusbe seen.

[0012] After investigating the expression by keratinocytes of lipase orcholesterol esterase activity, the inventors have identified lysosomialacid lipase (Human Lysosomial Acid Lipase or HLAL, Anderson R. A. etal., J. Biol. Chem., 266, 22479-84) and have shown, surprisingly, thatthis esterase is capable of cleaving certain precursors that are in theform of esterified active agents.

[0013] Consequently, the present invention relates to a bioprecursor offormula (I)

[0014] in which

[0015] A₁ and A₂ represent, independently of each other, a radicalderived from a molecule capable of being used in dermatology orcosmetology, and X and Y represent, independently of each other, ahydrogen atom, a hydroxyl group or a (C₁-C₂₀)alkyl group; and

[0016] n represents an integer between 0 and 10.

[0017] For the purpose of the present invention, the expression“compound capable of being used in dermatology or cosmetology” means,besides all of the agents defined in the above list, antibiotics, forinstance retronidazole, erythromycin, tetracycline and clindamycin,antibacterial agents, nonsteroidal antiinflammatory agents and vitamins.

[0018] In one particular embodiment of the invention, the moleculecapable of being used in dermatology or cosmetology hasantiinflammatory, antibacterial, antibiotic or vitamin activity.

[0019] In another particular embodiment of the invention, A₁ and A₂represent, independently of each other, an ascorbyl, cholecalciferyl,retinyl or tocopheryl radical.

[0020] In one particularly advantageous embodiment of the invention, A₁represents a tocopheryl radical and A₂ represents a radical chosen fromthe group comprising retinyl, cholecalciferyl and ascorbyl radicals.

[0021] In an even more advantageous embodiment according to theinvention, the compound of formula (I) is chosen from the groupconsisting of tocopheryl retinyl succinate, tocopheryl cholecalciferylsuccinate and tocopheryl ascorbyl succinate.

[0022] The present invention also covers pharmaceutical or cosmeticcompositions for topical use containing at least one bioprecursor offormula (I) combined with a vehicle that is suitable for percutaneousadministration.

[0023] In accordance with the present invention, when said compositionis applied to the skin, the complex undergoes an enzymatic hydrolysis ofesterase type leading to the release of the active principle, saidactive principle being released in a delayed manner, without anyaccumulation in the various layers of the skin.

[0024] The compositions according to the invention contain from 0.001%to 10% by weight and preferably 0.01% to 0.1% by weight of bioprecursorsrelative to the total weight of the composition.

[0025] They may be in the form of an oil-in-water (O/W) or water-in-oil(W/O) emulsion. They may also be in the form of spherules, for instanceliposomes, nanocapsules or nanospheres.

[0026] When the compositions are emulsions, the proportion of the fattyphase ranges from 5% to 80% by weight and preferably from 5% to 50% byweight relative to the total weight of the composition. The oils,emulsifiers and coemulsifiers used in these compositions, in emulsionform, are chosen from those conventionally used in cosmetics. Theemulsifier and the coemulsifier are present in the compositions in aproportion ranging from 0.3% to 10% by weight relative to the totalweight of the composition.

[0027] The compositions according to the invention may also containacceptable cosmetic or dermatological additives. These additives may be,in particular, antioxidants, other bioprecursors of these antioxidants,for instance δ-tocopheryl glucopyranoside, surfactants, fattysubstances, moisturizers, preserving agents, fragrances, gelling agents,chelating agents, pigments, for instance titanium oxide, screeningagents and free vitamins.

[0028] The bioprecursors of formula (I) are prepared via techniquesknown to those skilled in the art.

[0029] In one particularly advantageous embodiment of the process, acompound of formula (II)

A₁-H   (II)

[0030] in which A₁ is as defined above,

[0031] is reacted with a compound of formula (III)

[0032] in which X and Y are as defined above,

[0033] in a mixture containing a solvent, for instance anhydrousdichloromethane, triethylamine, II, III, dicyclohexylcarbodiimide (DCC)and dimethylaminopyridine (DMAP), to give a compound of formula (IV)

[0034] which compound is reacted under the same conditions as above witha compound of formula (V)

A₂-H   (V)

[0035] to give the compound of formula (I).

[0036] In another advantageous embodiment of the process according tothe invention, the compound of formula (II) is reacted with an activatedform of the compound of formula (III), for example succinic anhydride.

[0037] The advantages of this bioprecursor strategy are the following:

[0038] stabilization of the active agent by means of neutralizing themost reactive hydroxyl function (vitamins D, E or A). Due to the size ofthe esterase activity in the live layers of the epidermis and to itsvirtual absence in the horny layer (U. K. Jain et al., Proceed. Intern.Symp. Control. Rel. Bioact. Mater. (1995), 22, 702-703), the precursorsthat represent the stabilized form of the active principles arepreserved throughout the slow migration through the horny layer, whichcorresponds to the part that is the most exposed to oxidative stress (UVand ozone) (G. Valacchi et al., FEBS Letters (2000), 446, 165-168);

[0039] release at a controlled rate (taking into account the veryprecise regulation of the skin physiology) and reservoir effect.

[0040] Furthermore, targeted release from the stratum granulosum at thelevel of the plasma membranes of the keratinocytes is obtained (M. P.Mora et al., Chem. Phys. Lipids (1999), 101, 255-265), i.e. immediatelyat the start of the live part of the epidermis.

[0041] The precursor, after migration into the first layers of the liveepidermis, i.e. into the stratum granulosum, is recognized as apseudosubstrate via the involved esterase activity, which is responsiblefor the hydrolysis of the two ester functions. Two conjugate, additiveor even synergistic, effects are thus obtained using a singleformulation, this formulation facilitating migration.

[0042] Thus, the tocopherol-ascorbic acid combination is particularlyadvantageous, since the ascorbic acid regenerates the tocopherol afterits oxidation, thus increasing its antioxidant efficacy.

[0043] The structure of the precursors according to the inventionensures good stability throughout the passage through the layer andrelease of the active agents into the live layers of the epidermis, withkinetics that ensure effective cleavage and an effect with remanenceover time.

[0044] The penetration through the skin is associated with the Kd of thecompounds (Agache P. et al., Ed. Tech. Encycl. Med. Chir. (1995),12-235-C-30,1-10); however, the structure of the precursors according tothe invention also makes it possible to modulate the penetration of thepseudo-substrate active agents by virtue of the presence of X and Ywhich represent either hydroxyl groups, and are thus hydrophilic, or(C₁-C₂₀)alkyl groups, and are thus lipophilic, which make it possible toobtain an amphiphilic compound capable of penetrating in an appreciableamount via passive diffusion.

[0045] The examples that follow illustrate the invention without,however, limiting it.

EXAMPLE 1O-(4-Oxo-4-{[2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)-3,4-dihydro-2H-chromen-6-yl]oxy}butanoyl)retinolor tocopheryl retinyl succinate (CV-105)

[0046]

1.1. Methyl2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)-3,4-dihydro-2H-chromen-6-ylsuccinate (CV-104)

[0047]

[0048] Two synthetic methods were developed, starting either withsuccinic anhydride or with succinic acid.

[0049] According to the first method, α-tocopherol or vitamin E (2.15 g,5 mmol) and succinic anhydride (750 mg, 7.5 mmol, 1.5 eq) are dissolvedin 20 ml of anhydrous dichloromethane (CH₂Cl₂). Dimethylaminopyridine(DMAP) (305 mg, 2.5 mmol, 0.5 eq) and anhydrous triethylamine (0.7 ml, 1eq) are added thereto and the reaction is monitored by thin-layerchromatography (tlc) (Et₂O/petroleum ether (PE) 2:3 or ethyl acetate/PE1:1). The reaction is generally complete after reacting overnight, andthe mixture is thus filtered and then washed with aqueous 5%hydrochloric acid (HCl). The organic phase is dried over MgSO₄ and thenevaporated to give a yellow oil (about 3 g) to be purified.

[0050] According to the second method, succinic acid, (590 mg, 5 mmol),dicyclohexylcarbodiimide (DCC) (1.03 g, 1 eq) and DMAP (61 mg, 0.5 mmol,10%) are dissolved in 20 ml of anhydrous CH₂Cl₂ with ultrasonication for10-15 minutes, after which a-tocopherol or vitamin E (2.15 g, 5 mmol, 1eq) dissolved in 10 ml of anhydrous CH₂Cl₂ is added thereto. Thereaction is monitored by tlc (Et₂O/PE 2:3 or EtOAc/PE 1:1). The mixtureis thus filtered and then washed with aqueous 5% HCl and the organicphase is dried over MgSO₄ and then evaporated to give a yellow oil to bepurified.

[0051] In both cases, the product is purified by flash chromatography(2.5 cm×16 cm column, eluent Et₂O/PE 2:3, 10-15 ml fractions). Thedeposition of the pasty oil may take place as a solid deposit or inCH₂Cl₂. The first method gives 2.26 g of pure CV-104, i.e. 85% yield,and the second method gives 1.95 g, i.e. 73% yield of a pale yellow oilthat hardens at −20° C. and can give a white powder.

[0052] Rf (Et₂O/PE 2:3): 0.39. ¹H NMR (CDCl₃, 250 MHz):2.87 (dt, 4H,H—(C_(ac succ)) ²J=21, ³J=6.6); 2.58 (t, 4H, H—(C₄, C₃), ³J=6); 2.08,2.01, 1.97 (3 s, 9H, CH₃—(C₅), CH₃—(C₇), CH₃—(C₈)), 1.6-1 (broadmultiplet, 24H, CH₃—(C₁)+9×CH₂, 3×CH tocopherol), 0.88, 0.84 (2 s, 12H,4×CH₃ tocopherol). ¹³C NMR (CDCl₃, 50 MHz): 177.51, 170.96 (s,C═O_(acid)+C═O_(ester)); 149.48 (s, C_(8a)); 140.44 (s, C₆); 126.73 (s,C₇); 125.00 (s, C₅); 123.10 (s, C₈); 117.45 (s, C_(4a)); 75.11 (s, C₂) ;39.42 (t, C_(1′)); 37.45 (t, C_(7′)+C_(9′)+C_(3′)+C_(5′)+C_(11′)); 32.83(d, C_(8′)+C_(4′)+C_(12′)); 28.97, 28.68, 24.88, 24.50, 21.08, 20.64(C_(10′)+C₆ _(6′)+C_(2′)+C₄+CH_(2 ac succ)); 28.04 (CH₃—(C₂)); 22.69(C_(13′)); 19.74, 12.7, 12.18, 12.10, 11.99(CH—(C_(12′)+C_(8′)+C_(4′))+CH₃—(C₈+C₇+C₅)+CH₃—(C₁)). IR (NaCl): 2924,2856, 2735, 2638, 2540, 1746, 1694, 1455, 1421, 1378, 1323, 1246, 1155,1106, 919, 853, 799, 728. MS (CI, NH₃): 548 ([MNH₄]⁺, 100); 531 ([MH]⁺,11.3); 530 ([M]⁺, 3.4). UV (CH₃CN): 286 (0.047 at a concentration of 14μg/ml); 203 (0.61 at a concentration of 14 μg/ml). EA for C₃₃H₅₄O₅(530.78): calc. C, 74.67; H, 10.25; exp. C, 74.85, H, 10.26.

1.2. Tocopheryl retinyl succinate (CV-105)

[0053]

[0054] CV-104 prepared in example 1.1 (356 mg, 0.67 mmol) is dissolvedin 20 ml of anhydrous CH₂Cl₂, and DCC (138 mg, 1 eq) and DMAP (20 mg)are directly added thereto. After 10 minutes, a precipitate ofdichlorohexylurea (DCU) has already formed, the anhydride of CV-104having necessarily been formed. After 20 minutes, retinol-vitamin A (192mg, 1 eq) dissolved in 5 ml of anhydrous CH₂Cl₂ is added. The reaction,performed in the absence of light, is monitored by tic (CH₂Cl₂/PE 2:3):a new, less polar product forms. After reacting overnight, the solventis filtered and then evaporated off. The product is purified by flashchromatography with EtOAc/PE (2:3) to give a yellow oil (266 mg; 50%yield). A second purification is performed by HPLC (20 g of silica 35,eluent Et₂O/PE 1:9).

[0055] Starting with 130 mg of the first purified batch, 72 mg of atranslucent oil (CV-105) are obtained, i.e. a 28% yield.

EXAMPLE 2 Tocopheryl cholecalciferyl succinate(CV-125)

[0056]

[0057] CV-104 prepared in example 1.1 (423 mg, 0.798 mmol) is dissolvedin 10 ml of anhydrous CH₂Cl₂, and DCC (181 mg, 1.1 eq) and DMAP (20 mg)are directly added thereto. After 20 minutes, vitamin D₃ (307 mg, 1 eq)dissolved in 10 ml of anhydrous CH₂Cl₂ is added. The reaction, performedin the absence of light, is monitored by tlc (EtOAc/PE 2:8 or 5:95): anew, less polar product forms. After reaction overnight, the solvent isfiltered and then evaporated off. The product is purified by flashchromatography with EtOAc/PE (5:95) as eluent, 2×12 cm column, 6-8 mlfractions.

[0058] Fractions 4 to 10 are evaporated to give 253 mg of tocopherylcalciferyl succinate (CV-125) as a translucent oil (35% yield).

[0059] Rf (EtOAc/PE 2:8): 0.91; (EtOAc/PE 5:95): 0.32. ¹H NMR (CDCl₃,250 MHz): 6.22 (d, 1H, H—(C₇), ³J₇₋₈=11.2); 6.04 (d, 1H, H—(C₈),³J₈₋₇=11.2); 5.07 (s, 1H, CH₂—(C₄)); 4.98 (m, 1H, H—(C₁)); 4.85 (d, 1H,CH₂—(C₄)); 2.92 (dd, 2H, CH_(2-succ), ²J=16, ³J=6.8); 2.75 (m, 3H,CH_(2-succ)+CH—(C₄), ²J=16, ³J=6.8); 2.60 (m, 2H, CH—(C₆)+CH—(C₄)); 2.4(m, 2H, CH—(C₆)+H—(C₁₇)); 2.09, 2.03, 1.99 (3 s, 9H, CH₃—(C₅), CH₃—(C₇),CH₃—(C₈)), 1.3-0.9 (broad multiplet, 47H, 11×CH_(2-vitE), 3×CH—(C_(12′),C_(4′), C_(8′))+11×CH₂-_(vitD3)); 0.89 and 0.87 (2 s, 21H,4×CH₃—(C_(12′), C_(4′), C_(8′))+C₂₅); 0.55 (s, 3H, CH₃—(C₁₃)). ¹³C NMR(CDCl₃, 50 MHz): 171.72, 171.07 (s, 2×C═O_(ester)); 149.47 (s, C₅);144.64 (s, C₆); 142.55 (s, C_(8a)); 140.50 (s, C₉); 134.23 (s, C₄);126.76 (s, C₇); 125.00 (s, C₅); 123.06 (s, C₈); 122.61 (d, C₇); 117.53(d, C₈); 117.38 (s, C_(4a)); 112.81 (t, CH₂—(C₄)); 75.08 (s, C₂); 72.28(d, C₁); 56.66 (d, C₁₇); 56.43 (d, C₁₄); 45.97 (s, C₁₃); 42.19 (t, C₁₂);36.20, 32.84, 32.77 (d, C_(8′)+C_(4′)+C_(12′)); 40.62, 39.57, 39.44,37.47, 32.23, 31.99, 31.12, 29.50, 29.12, 28.96, 28.08, 27.76(t,C_(1′+C)₃+C_(7′)+C_(9′)+C_(3′)+C_(5′)+C_(11′)+C₁₅+C₁₀+C₆+C₂+C₃+C₁₈₋₂₃+2×CH_(2 ac succ)),24.89, 24.52, 23.95, 23.64, 22.29, 21.11, 20.67 (t,C_(10′)+C_(6′)+C_(2′)+C₄+C₂₄+C₁₆+C₁₁); 22.91, 22.81, 22.71 (q,CH₃—(C₂+2×C_(13′)); 19.76, 18.92, 13.05, 12.19, 12.05, 11.89 (q,CH₃—(C_(8′)+C_(4′))+CH₃—(C₈+C₇+C₅)+C₂₅+CH₃—(C₂)). IR (NaCl): 2950, 2867,2119, 1758, 1736, 1463, 1412, 1377, 1240, 1202, 1146, 1110, 1079, 996,734. MS (CI, NH₃): 914 ([MNH₄]⁺, 100); 897 ([MH]⁺, 2.86); 896 ([M]⁺,2.71). EA for C₆₀H₉₆O₅ (896): calc. C, 80.30; H, 10.78; exp. C, 77.36;H, 10.26.

EXAMPLE 3 Tocopheryl ascorbyl succinate (CV-106) 3.1. Protected vitaminC (CV-100)

[0060]

[0061] 250 μl of acetyl chloride are added to a suspension of vitamin C,or ascorbic acid (3 g, 17 mmol) in 30 ml of acetone. The solutionbecomes clear and a white precipitate then forms. After reactionovernight, the precipitate is filtered off and then rinsed with ice-coldethyl acetate. The powder obtained is then dried to give 2.96 g (13.7mmol) of protected vitamin C (CV-100), i.e. an 80.6% yield.

3.2. Tocopheryl ascorbyl succinate (CV-106)

[0062]

[0063] CV-104 prepared in example 1.1 (265 mg, 0.5 mmol) is dissolved in10 ml of anhydrous EtOAc over about 15 minutes. In parallel, CV-100prepared in example 3.1 (108 mg, 0.5 mmol, 1 eq) is dissolved in 2 ml ofanhydrous tetrahydrofuran (THF) (or 0.2 ml of dimethylformamide, orDMF), followed by 5 ml of anhydrous ethyl acetate, and the solubility ischecked after 5-10 minutes. The solution of CV-100 is added to that ofCV-104, the solution remains clear, and DMAP (catalytic) and DCC (113mg, 0.55 mmol, 1.1 eq) are added thereto. The precipitate formsimmediately and the reaction is monitored by tlc (CH₂Cl₂/EtOAc/MeOH8:1:1). The reaction is virtually complete after 8 hours.

[0064] The mixture is filtered and washed very quickly with 0.1N HCl,and the organic phase is dried over MgSO₄ and then evaporated to giveCV-106 in the form of a white foam (386 mg).

[0065] The coupling appears to take place mainly at C2 rather than at C3of vitamin C. Specifically, the NMR data are more in accordance with thepreviously described C2 esters (Cabral J., J. Org. Chem. (1988), 53,5742-50).

[0066] The product is purified by HPLC (30 mg) column of silica 15-25,eluent CH₂Cl₂/EtOAc/NEt₃ (9:1:0.5%) then CH₂Cl₂/EtOAc/NEt₃/MeOH(9:1:0.5:2%).

[0067] Appearance: white foamy powder

[0068] Rf (EtOAc/CH₂Cl₂/MeOH 1:8:1): 0.38; (EtOAc/CH₂Cl₂/MeOH 1:8:2):0.48. ¹H NMR (CDCl₃, 250 MHz): 4.66 (d, 1H, C_(4 vitC)) ; 4.39 (ddd, 1H,C_(5 vitC)) ; 4.1 (td, 2H, C_(6 vitC), ³J₆₋₅=7.2, ²J_(6-6′)=19); 2.92,2.76 (2t, 4H, H—(C_(ac succ)), ³J=6, 6); 2.58 (t, 2H, H—(C4), ³J=6);2.08, 2.0, 1.97 (3 s, 9H, CH₃—(C₅), CH₃—(C₇), CH₃—(C₈)); 1.8-1.7 (m, 2H,H—(C₃)); 1.7-1.09 (broad multiplet, 23H, 10×CH₂, 3×CH tocopherol); 0.87,0.85 (2 s, 12H, 4×CH₃ tocopherol). ¹³C NMR (CDCl₃, 50 MHz): 171.65,171.12 (s, 2×C═O_(ester)) ; 159.12 (s, C_(3 vitC)); 149.61 (s, C₆);140.46 (s, C_(8a)); 126.58 (s, C₇) ; 124.89 (s, C₅) ; 123.16 (s, C₈);117.54 (s, C_(4a)); 114.39 (s, C_(2 vitC)) 110.57 (s, C_(7 vitc)); 75.16(s, C₂); 75.10 (d, C_(4 vitC)) ; 73.68 (d, C_(5 vitC)); 65.32 (t,C_(6 vitC)); 39.43 (t, C_(1′)); 37.46 (t, C₃); 32.84, 32.76, 29.00 (d,C_(8′)+C_(4′)+C_(12′)); 31.09, 29.78, 28.99, 28.90, 28.70, 28.57, 24.88,24.51, 21.09, 20.65 (t,C_(7′)+C_(9′)+C_(3′)+C_(5′)+C_(11′)+C_(10′)+C_(6′)+C_(2′)+C₄+2×CH_(2 ac succ));25.86, 25.61 (q, C_(8 and 8′ vitC)); 21.09, 20.65 (q,CH₃—(C₂)+2×C_(13′)); 22.81, 22.72, 13.00, 12.15, 11.89 (q,CH₃—(C_(8′)+C_(4′))+CH₃—(C₈+C₇+C₅)). IR (NaCl) : 3248, 2929, 2856, 1756,1670, 1605, 1453, 1409, 1374, 1322, 1256, 1213, 1141, 1066, 885, 852,820, 736, 700. MS (CI, NH₃): 746 ([MNH₄]⁺, 96); 728 ([M]⁺, 2.6); 612(6.7); 548 [MNH₄]⁺ of CV-104 (20.3); 423 (16); 234 [MNH₄]⁺ of CV-100(59). EA for C₄₂H₆₄O₁₀ (728): calc. C, 69.20; H, 8.85; exp. C, 67.17; H,8.83.

EXAMPLE 4 Enzymatic hydrolysis 4.1. Procedure

[0069] 150 μl of a 1 mM solution in dimethyl sulphoxide (DMSO) areplaced in a dish containing an HaCaT keratinocyte line (75 cm²) in 15 mlof serum alone. The cells are placed in the incubator at 37° C. for 24hours. The medium is extracted with 15 ml of ethyl acetate. The organicphase is then isolated and evaporated off.

[0070] The cells are extracted by sonication into 2×15 ml of an ice-coldmixture consisting of chloroform and methanol (1:2.5). Aftercentrifugation, the organic phase collected is evaporated to dryness.For each test, a control is performed on a dish containing cells and asubstrate-free medium to take account of a possible chemical degradationof the substrate.

[0071] The presence of esterase activity in the human keratinocytes ischecked by means of a substrate, 4-methylumbelliferyl palmitate. Theprecursor according to the invention, used as pseudosubstrate, is thetocopheryl retinyl succinate prepared according to example 1.

4.2. Results

[0072] The results are collated in the following table: Degree ofhydrolysis in 24 Substrate hours of incubation Released part4-Methylumbelliferyl 2.7% ± 2% 4-methylumbel- palmitate liferoneTocopheryl retinyl   5% ± 3% vitamins A succinate and E

[0073] The values obtained show a simultaneous release of vitamins E andA from the tocopheryl retinyl succinate. These results confirm the verygood cleavage kinetics in the case of succinate esters via thekeratinocyte esterases. Furthermore, a release with a reservoir effectis observed, since the undegraded precursor is found in the sampletaken.

1. A bioprecursor of formula (I)

in which A₁ and A₂ represent, independently of each other, a radicalderived from a molecule capable of being used in dermatology orcosmetology; X and Y represent, independently of each other, a hydrogenatom, a hydroxyl group or a (C₁-C₂₀)alkyl group; and n represents aninteger between 0 and
 10. 2. The bioprecursor as claimed in claim 1,characterized in that the molecule capable of being used in dermatologyor cosmetology has antiinflammatory, antibacterial, antibiotic orvitamin activity.
 3. The bioprecursor as claimed in claim 1, in which:A₁ and A₂ represent, independently of each other, an ascorbyl,cholecalciferyl, retinyl or tocopheryl radical.
 4. The bioprecursor asclaimed in claim 3, characterized in that A₁ represents a tocopherylradical and A₂ represents a radical chosen from the group comprisingretinyl, cholecalciferyl and ascorbyl radicals.
 5. The bioprecursor asclaimed in claim 1, characterized in that it is chosen from the groupconsisting of tocopheryl retinyl succinate, tocopheryl cholecalciferylsuccinate and tocopheryl ascorbyl succinate.
 6. The bioprecursor asclaimed in claim 1, characterized in that it is chosen from


7. A pharmaceutical composition, characterized in that it contains atleast one bioprecursor as claimed in claim 1 combined with a vehiclethat is suitable for percutaneous administration.
 8. The pharmaceuticalcomposition as claimed in claim 7, characterized in that it containsfrom 0.001% to 10% by weight and preferably 0.01% to 0.1% by weight ofbioprecursors relative to the total weight of the composition.
 9. Thepharmaceutical composition as claimed in claim 7, characterized in thatit is in the form of an oil-in-water (O/W) or water-in-oil (W/O)emulsion.
 10. The pharmaceutical composition as claimed in claim 7,characterized in that it is in the form of spherules.
 11. Thepharmaceutical composition as claimed in claim 9, characterized in thatthe proportion of the fatty phase ranges from 5% to 80% by weight andpreferably from 5% to 50% by weight relative to the total weight of thecomposition.
 12. The pharmaceutical composition as claimed in claim 7,characterized in that it also contains acceptable cosmetic ordermatological additives.
 13. A process for preparing the bioprecursorsas claimed in claim 1, characterized in that a compound of formula (II)A₁-H   (II) in which A₁ is as defined in claim 1, is reacted with acompound of formula (III)

in which X and Y are as defined in claim 1, in a mixture containing asolvent, for instance anhydrous dichloromethane, triethylamine, II, III,dicyclohexylcarbodiimide (DCC) and dimethylaminopyridine (DMAP), to givea compound of formula (IV)

which compound is reacted under the same conditions as above with acompound of formula (V) A₂ -H   (V) to give the compound of formula (I).